Fuel homeostasis requires coordinating diverse pathways of intermediary metabolism, and both nutrition and disease play determinant roles in the selection and utilization of specific fuels. A nutritional perturbation of considerable recent interest is the omega-3 fatty acid class of marine lipids. Their lipid- lowering and other metabolic effects make them potentially attractive therapy for patients with diabetes mellitus, in whom the prevalence of both hyperlipemia and atherosclerosis is high. Studies by us and others have provided new insight into the lipid- lowering effects of fish oil, but have also raised the possibility that these fatty acids may worsen glucose tolerance in diabetics. In this proposal we compare the metabolic effects of dietary omega- 3 and omega-6 fatty acids and test three major hypotheses regarding the biochemical mechanisms of action of these nutrients in hypertriglyceridemic diabetics, namely 1) Omega-3 incorporation into lipids alters the metabolism of those lipids and their association with apolipoproteins, causing changes in the secretion of lipid transport particles into plasma and their reactions with enzymes and receptors involved with their metabolism. This will be tested by kinetic modeling and use of labeled glycerol, linoleate, eicosapentaenoate and leucine as endogenous tracers in patients stabilized on omega-6 or omega-3 diets. Biosynthesis and metabolism of triglyceride-rich lipoprotein and apoproteins will be studied. Lipoprotein will be isolated and their compositions characterized by ultracentrifugal and heparin-agarose subfractionation techniques. Plasma lipolytic activity will also be measured. 2) Omega-3 fatty acids inhibit hepatic lipogenesis and stimulate gluconeogenesis, due partly to redirection of shared precursors (e.g., glycerol) for these pathways. This postulate will be addressed by the tracer methodology outlined above and by the hyperinsulinemic, euglycemic clamp. By these combined endogenous lipid and glucose tracer techniques, we may discern the ability of an omega-3 diet to dissociate lipid synthesis from glycerol utilization and link this dissociation to increased glucose production. 3) Omega-3 fatty acids inhibit insulin secretion in Type II diabetics. This will be tested during omega- 3 and omega-6 ingestion by measuring the secretion of insulin, C- peptide and gastric inhibitory peptides (GIP) following oral and intravenous glucose and a mixed meal. We anticipate that direct or GIP-mediated suppression of insulin release may be an additional mechanism by which a fish oil diet impairs glucose metabolism in diabetic.